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The new england journal of medicine original article

The new england journal of medicine original article. Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes 28 Jul 2011. Chairperson: Dr. Sayta Ranjan Sutradhar Associate Professor and Head Department of Medicine Mymensingh Medical College

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The new england journal of medicine original article

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  1. The new england journal of medicine original article Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes 28 Jul 2011

  2. Chairperson: Dr. Sayta Ranjan Sutradhar Associate Professor and Head Department of Medicine Mymensingh Medical College Presenter: Dr. Md. Abdul Muqueet Assistant Professor and Head Department of Nephrology Mymensingh Medical College

  3. Pablo E. Pergola, M.D., Ph.D.,Philip Raskin, M.D., Robert D. Toto, M.D., Colin J. Meyer, M.D., J. Warren Huff, J.D., Eric B. Grossman, M.D., Melissa Krauth, M.B.A., Stacey Ruiz, Ph.D., Paul Audhya, M.D., Heidi Christ-Schmidt, M.S.E., Janet Wittes, Ph.D., and David G. Warnock, M.D.,

  4. Introduction: Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide. CKD in patients with diabetes is associated with chronic inflammation and oxidative stress.

  5. Bardoxolone Methyl Antioxidant inflammation modulator Keap1–Nrf2 pathway Up-regulation of cytoprotective genes Inhibiting the proinflammatory nuclear factor κB pathway

  6. Methods: Patients- CKD with T2DM eGFR-20 to 40 ml/min/1.73 ACE and/ ARB 8 wk

  7. Exclusion criteria: * Type 1 diabetes * Nondiabetic renal disease * HbA1c >10% * Hepatic dysfunction * Cardiovascular event

  8. Study Design: • 227 of 573 at 43 site USA • Placebo or Bardoxolone 25,75,150 once oraly 52 wk 1:1:1:1 ratio • Four period -3wk screening -8 wk dose adjustment -52 wk maintanence -4 wk follow up

  9. Patient stratified at randomization • eGFR <30 or ≥ 30 ml/min/1.73 • ACR ≤300 or > 300 mg/g • HbA1c < 7% or > 7% Patient safety monitored Written informed consent

  10. Procedures and Outcomes: • eGFR and routine lab test done on screening and every 4 wk • eGFR by 4 variable MDRD • Creatinine calibrated IDMS • Primary outcome eGFR change at 24 • Secondery outcome at 52 wk compared to placebo

  11. Exploratory outcomes: • Change eGFR at 52 wk • Time, % patients with a reduced eGFR of 25% or more • Change eGFR 4 wk after the last administration Bardoxolone • Change ACR from baseline • Change at 24, 52 wk compared to placebo for basic lab tests

  12. Statistical Analysis: • Here used a repeated-measures model to analyze the primary and secondary outcomes, with monthly measurement of the estimated GFR through 52 weeks as the response and with the baseline estimated GFR, ACR, and glycated hemoglobin level as continuous covariates.

  13. Statistical Analysis: • The model included all measurements up to the time of withdrawal from the study, regardless of the status of study-drug administration and categorical variables for treatment, week, and treatment-by-week inter -action. Within-patient correlation was modeled with a Toeplitz structure. • We used Kaplan–Meier methods to estimate the proportion of patients remaining event-free at time points of interest. The study groups were compared with the use of unstratified log-rank tests with unadjusted two-sided type I error rates.

  14. Results: Baseline variables are similar in 4 groups Mean age-67 yr Total 98% received ACE /or ARB Mean eGFR 32.4±6.9 ml/min/1.73 Normoalbuminuria-37% Microalbuminuria-29% Macroalbuminuria-34% Blood glucose levels well controlled

  15. Primaryand Secondary End Point • Bardoxolone group eGFR increases within 4 wk, peaked at 12 wk, stable through 52 wk • Primary End Point-24 wk (P<0.001 for all comparisons)

  16. Primaryand Secondary End Point • The difference in the change between the 25-mg group and the 75-mg group was significant (P=0.04), but the difference between the 75-mg group and the 150-mg group was not significant (P=0.54)

  17. Secondary End Point: 52 wk

  18. Primaryand Secondary End Point for placebo • There were no significant changes from baseline in the estimated GFR in the placebo group at 24 or 52 weeks

  19. Exploratory Outcomes: eGFR decreases at 52 wk completing therapy

  20. Exploratory Outcomes: • The proportion of patients with a reduction in the estimated GFR of 25% or more at 24 weeks was 13% (95% confidence interval [CI], 6 to 25) in the placebo group and 2% (95% CI, 1 to 6) in the combined bardoxolone methyl groups (P = 0.05)

  21. Exploratory Outcomes: • Four weeks after the last administration of the study drug (at 56 wks) eGFR changes

  22. Exploratory Outcomes: • In a post hoc sensitivity analysis increases in the estimated GFR were sustained for 52 weeks in the 75-mg and 150-mg groups but not in the 25-mg group

  23. Exploratory Outcomes: • At 24 wk significant decreases urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo • Inverse correlation changes in the eGFR

  24. Exploratory Outcomes: • In the 75-mg and 150-mg groups, there was a slight but significant increase in the ACR at 24 and 52 weeks • Changes in the ACR and estimated GFR were positively correlated at 52 weeks. • At 56 weeks, the ACR generally returned to the baseline level

  25. Adverse Events: • Muscle spasm- 42% in the 25-mg group 61% in the 75-mg group 59% in the 150-mg group, 18% in the placebo group (12 wk, calf, lactate dehydrogenage)

  26. Adverse Events: • Alanine aminotransferase- 71%, within 2 to 4 wks, 11% three times Not persistant, recur, bilirubin unchanged • Weight reduction- more pronounced in patients with an increased body-mass index at baseline independent of change eGFR

  27. Adverse Events: • Discontinuations and withdrawal- • Sixteen patients- muscle spasms six patients nausea and vomiting in three patients weight change in three patients decreased appetite in two patients One death occurred

  28. Discussion: • Bardoxolone methyl activates the Keap1–Nrf2 pathway- regulates inflammation and oxidative stress • Murine model Nrf2 delition • AKI- Bardoxolone Nrf2, heme oxygenase 1, decrease reactive oxygen reduction in inflammation decrease urea nitrogen amelioration of both glomerular and tubular in -jury was observed

  29. Discussion: • Sustained, significant improvement, short- long term, remained after stop--decrease inflamation and oxidative stress • Independently of changes in albumin excretion • Absence of significant decline in Egfr placebo BP,HbA1c well control,not macroalbuminuric • Effects on multiple blood chemical values • ACR significant increase, discontinution decrease

  30. Discussion: • Nrf2 expression ubiquitous-transient, self-limited elevations in aminotransferase • Muscle spasm- calf, glucose uptake

  31. Limitations: • many patients did not reach the target dose • Measurement of the GFR to validate these results would be important • The confirmation of clinical benefit will require a larger, long-term study involving the assessment of clinical outcomes

  32. Conclusions: • Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. • The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD.

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